Structurally similar allosteric modulators of α7 nicotinic acetylcholine receptors exhibit five distinct pharmacological effects.

Activation of nicotinic acetylcholine receptors (nAChRs) is associated with the binding of agonists such as acetylcholine to an extracellular site that is located at the interface between two adjacent receptor subunits. More recently, there has been considerable interest in compounds, such as positive and negative allosteric modulators (PAMs and NAMs), that are able to modulate nAChR function by binding to distinct allosteric sites. Here we examined a series of compounds differing only in methyl substitution of a single aromatic ring. This series of compounds includes a previously described α7-selective allosteric agonist, cis-cis-4-p-tolyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (4MP-TQS), together with all other possible combinations of methyl substitution at a phenyl ring (18 additional compounds). Studies conducted with this series of compounds have revealed five distinct pharmacological effects on α7 nAChRs. These five effects can be summarized as: 1) nondesensitizing activation (allosteric agonists), 2) potentiation associated with minimal effects on receptor desensitization (type I PAMs), 3) potentiation associated with reduced desensitization (type II PAMs), 4) noncompetitive antagonism (NAMs), and 5) compounds that have no effect on orthosteric agonist responses but block allosteric modulation (silent allosteric modulators (SAMs)). Several lines of experimental evidence are consistent with all of these compounds acting at a common, transmembrane allosteric site. Notably, all of these chemically similar compounds that have been classified as nondesensitizing allosteric agonists or as nondesensitizing (type II) PAMs are cis-cis-diastereoisomers, whereas all of the NAMs, SAMs, and type I PAMs are cis-trans-diastereoisomers. Our data illustrate the remarkable pharmacological diversity of allosteric modulators acting on nAChRs

Synthesis of Novel Allosteric Agonists and Allosteric Modulators for Nicotinic Acetylcholine Receptors

In healthy individuals, the α7 and α4β2 nAChRs are concentrated in regions of the brain involved with learning, cognition and memory, which are relevant to diseases such as Alzheimer’s disease. Hence, these receptors have become significant from a pharmacological and drug discovery perspective. The tetrahydroquinoline compound 4BP-TQS has been reported to act as a potent allosteric agonist on the α7 nAChR. The natural product desformylflustrabromine is able to act as a positive allosteric modulator (PAM) on the α4β2 nAChR. This thesis describes the development of synthetic routes directed towards 4BP-TQS and desformyflustrabromine analogues, and their pharmacological effects on α7 and α4β2 nAChRs. In the first half of the project a total of 51 analogues of 4BP-TQS were synthesized by performing a multicomponent reaction (MCR) between a substituted benzaldehyde, an aniline and an activated alkene. The pharmacological properties of these compounds were then studied by our collaborators in UCL pharmacology. These compounds exhibited interesting and wide ranging pharmacological properties with individual compounds acting as either allosteric agonists, antagonists, type I or type II positive allosteric modulators or allosteric antagonists of 4BP-TQS. The second part of the project involved the development of new chemistry directed towards the synthesis of desformylflustrabromine analogues. Initial work focused on the investigation of a novel Pd-catalysed allylation procedure for introducing an allyl group at the C-2 position of indole. Although the desired transformation was not successfully achieved, a novel regioselective Pd-catalysed C-3 diallylation of substituted indoles was discovered. The diallylated products were shown to be versatile intermediates which could undergo a variety of different reactions. By subjecting the diallylated products to ring-closing metathesis, a series of spirocyclic alkaloid-like structures were obtained in excellent yields. It was also demonstrated that the diallylated products could be desymmetrized using a proline-catalysed Mannich reactions to give enantioenriched products

Rapid assembly of functionalised spirocyclic indolines by palladium-catalysed dearomatising diallylation of indoles with allyl acetate

Herein, we report the application of allyl acetate to the palladium-catalysed dearomatising diallylation of indoles. The reaction can be carried out by using a readily available palladium catalyst at room temperature, and can be applied to a wide range of substituted indoles to provide access to the corresponding 3,3-diallylindolinines. These compounds are versatile synthetic intermediates that readily undergo Ugi reactions or proline-catalysed asymmetric Mannich reactions. Alternatively, acylation of the 3,3-diallylindolinines with an acid chloride or a chloroformate, followed by treatment with aluminium chloride, enables 2,3-diallylindoles to be prepared. By using ring-closing metathesis, functionalised spirocyclic indoline scaffolds can be accessed from the Ugi products, and a dihydrocarbazole can be prepared from the corresponding 2,3-diallylindole. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Biodiesel production from camelina oil: Present status and future perspectives

Camelina sativa (L.) Crantz is an oilseed crop with favorable potentials for biodiesel production, such as the high plant yield, high oil content in the seed, high net energy ratio, and low oil production cost. This review paper deals with the present state and perspectives of biodiesel production from camelina oil. First, important issues of camelina seed pretreatment and biodiesel production are reviewed. Emphasis is given to different biodiesel technologies that have been used so far worldwide, the economic assessment of the camelina oil biodiesel (COB) production, the camelina-based biorefineries for the integrated biodiesel production, the COB life cycle analysis, and impact human health and ecosystem. Finally, the perspectives of COB production from the techno-economic and especially genetic engineering points of view are discussed

Highly efficient xylem transport of arsenite in the arsenic hyperaccumulator Pteris vittata

The hyperaccumulator Pteris vittata translocates arsenic (As) from roots to fronds efficiently, but the form of As translocated in xylem and the main location of arsenate reduction have not been resolved. Here, P. vittata was exposed to 5 mu M arsenate or arsenite for 1-24 h, with or without 100 mu M phosphate. Arsenic speciation was determined in xylem sap, roots, fronds and nutrient solutions by high-performance liquid chromatography (HPLC) linked to inductively coupled plasma mass spectrometry (ICP-MS). The xylem sap As concentration was 18-73 times that in the nutrient solution. In both arsenate- and arsenite-treated plants, arsenite was the predominant species in the xylem sap, accounting for 93-98% of the total As. A portion of arsenate taken up by roots (30-40% of root As) was reduced to arsenite rapidly. The majority (c. 80%) of As in fronds was arsenite. Phosphate inhibited arsenate uptake, but not As translocation. More As was translocated to fronds in the arsenite-treated than in the arsenate-treated plants. There was little arsenite efflux from roots to the external solution. Roots are the main location of arsenate reduction in P. vittata. Arsenite is highly mobile in xylem transport, possibly because of efficient xylem loading, little complexation with thiols in roots, and little efflux to the external medium

Rapid reduction of arsenate in the medium mediated by plant roots

Microbes detoxify arsenate by reduction and efflux of arsenite. Plants have a high capacity to reduce arsenate, but arsenic efflux has not been reported. Tomato (Lycopersicon esculentum) and rice (Oryza sativa) were grown hydroponically and supplied with 10 mu M marsenate or arsenite, with or without phosphate, for 1-3 d. The chemical species of As in nutrient solutions, roots and xylem sap were monitored, roles of microbes and root exudates in As transformation were investigated and efflux of As species from tomato roots was determined. Arsenite remained stable in the nutrient solution, whereas arsenate was rapidly reduced to arsenite. Microbes and root exudates contributed little to the reduction of external arsenate. Arsenite was the predominant species in roots and xylem sap. Phosphate inhibited arsenate uptake and the appearance of arsenite in the nutrient solution, but the reduction was near complete in 24 h in both -P- and +P-treated tomato. Phosphate had a greater effect in rice than tomato. Efflux of both arsenite and arsenate was observed; the former was inhibited and the latter enhanced by the metabolic inhibitor carbonylcyanide m-chlorophenylhydrazone. Tomato and rice roots rapidly reduce arsenate to arsenite, some of which is actively effluxed to the medium. The study reveals a new aspect of As metabolism in plants

Structural and functional insights into the candidate genes associated with different developmental stages of flag leaf in bread wheat (Triticum aestivum L.)

Grain yield is one of the most important aims for combating the needs of the growing world population. The role of development and nutrient transfer in flag leaf for higher yields at the grain level is well known. It is a great challenge to properly exploit this knowledge because all the processes, starting from the emergence of the flag leaf to the grain filling stages of wheat (Triticum aestivum L.), are very complex biochemical and physiological processes to address. This study was conducted with the primary goal of functionally and structurally annotating the candidate genes associated with different developmental stages of flag leaf in a comprehensive manner using a plethora of in silico tools. Flag leaf-associated genes were analyzed for their structural and functional impacts using a set of bioinformatics tools and algorithms. The results revealed the association of 17 candidate genes with different stages of flag leaf development in wheat crop. Of these 17 candidate genes, the expression analysis results revealed the upregulation of genes such as TaSRT1-5D, TaPNH1-7B, and TaNfl1-2B and the downregulation of genes such as TaNAP1-7B, TaNOL-4D, and TaOsl2-2B can be utilized for the generation of high-yielding wheat varieties. Through MD simulation and other in silico analyses, all these proteins were found to be stable. Based on the outcome of bioinformatics and molecular analysis, the identified candidate genes were found to play principal roles in the flag leaf development process and can be utilized for higher-yield wheat production. Copyright © 2022 Mehla, Kumar, Kapoor, Singh, Sihag, Sagwal, Balyan, Kumar, Ahalawat, Lakra, Singh, Pesic, Djalovic, Mir and Dhankher

The role of the rice aquaporin Lsi1 in arsenite efflux from roots

When supplied with arsenate (As(V)), plant roots extrude a substantial amount of arsenite (As(III)) to the external medium through as yet unidentified pathways. The rice (Oryza sativa) silicon transporter Lsi1 (OsNIP2;1, an aquaporin channel) is the major entry route of arsenite into rice roots. Whether Lsi1 also mediates arsenite efflux was investigated. Expression of Lsi1 in Xenopus laevis oocytes enhanced arsenite efflux, indicating that Lsi1 facilitates arsenite transport bidirectionally. Arsenite was the predominant arsenic species in arsenate-exposed rice plants. During 24-h exposure to 5 mu M arsenate, rice roots extruded arsenite to the external medium rapidly, accounting for 60-90% of the arsenate uptake. A rice mutant defective in Lsi1 (lsi1) extruded significantly less arsenite than the wild-type rice and, as a result, accumulated more arsenite in the roots. By contrast, Lsi2 mutation had little effect on arsenite efflux to the external medium. We conclude that Lsi1 plays a role in arsenite efflux in rice roots exposed to arsenate. However, this pathway accounts for only 15-20% of the total efflux, suggesting the existence of other efflux transporters

Enhanced production of multi-strange hadrons in high-multiplicity proton-proton collisions

At sufficiently high temperature and energy density, nuclear matter undergoes a transition to a phase in which quarks and gluons are not confined: the quark-gluon plasma (QGP)(1). Such an exotic state of strongly interacting quantum chromodynamics matter is produced in the laboratory in heavy nuclei high-energy collisions, where an enhanced production of strange hadrons is observed(2-6). Strangeness enhancement, originally proposed as a signature of QGP formation in nuclear collisions(7), is more pronounced for multi-strange baryons. Several effects typical of heavy-ion phenomenology have been observed in high-multiplicity proton-proton (pp) collisions(8,9), but the enhanced production of multi-strange particles has not been reported so far. Here we present the first observation of strangeness enhancement in high-multiplicity proton-proton collisions. We find that the integrated yields of strange and multi-strange particles, relative to pions, increases significantly with the event charged-particle multiplicity. The measurements are in remarkable agreement with the p-Pb collision results(10,11), indicating that the phenomenon is related to the final system created in the collision. In high-multiplicity events strangeness production reaches values similar to those observed in Pb-Pb collisions, where a QGP is formed.Peer reviewe

Constraints on jet quenching in p-Pb collisions at root s(NN)=5.02 TeV measured by the event-activity dependence of semi-inclusive hadron-jet distributions

CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFINEP - FINANCIADORA DE ESTUDOS E PROJETOSFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOThe ALICE Collaboration reports the measurement of semi-inclusive distributions of charged-particle jets recoiling from a high-transverse momentum trigger hadron in p-Pb collisions at root s(NN) = 5.02TeV. Jets are reconstructed from charged-particle tracks using the anti-k(T) algorithm with resolution parameter R = 0.2 and 0.4. A data-driven statistical approach is used to correct the uncorrelated background jet yield. Recoil jet distributions are reported for jet transverse momentum 15 < p(T,jet)(ch) < 50 GeV/c and are compared in various intervals of p-Pb event activity, based on charged-particle multiplicity and zero-degree neutral energy in the forward (Pb-going) direction. The semi-inclusive observable is self-normalized and such comparisons do not require the interpretation of p-Pb event activity in terms of collision geometry, in contrast to inclusive jet observables. These measurements provide new constraints on the magnitude of jet quenching in small systems at the LHC. In p-Pb collisions with high event activity, the average medium-induced out-of-cone energy transport for jets with R = 0.4 and 15 < p(T,jet)(ch) < 50 GeV/c is measured to be less than 0.4 GeV/c at 90% confidence, which is over an order of magnitude smaller than a similar measurement for central Pb-Pb collisions at root s(NN) = 2.76 TeV. Comparison is made to theoretical calculations of jet quenching in small systems, and to inclusive jet measurements in p-Pb collisions selected by event activity at the LHC and in d-Au collisions at RHIC.78395113CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFINEP - FINANCIADORA DE ESTUDOS E PROJETOSFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFINEP - FINANCIADORA DE ESTUDOS E PROJETOSFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOSem informaçãoSem informaçãoSem informaçãoAgências de fomento estrangeiras apoiaram essa pesquisa, mais informações acesse artig